Cotransplantation of preactivated mesenchymal stem cells improves intraportal engraftment of islets by inhibiting liver natural killer cells in mice

Abstract

Abbreviations: Cas9, CRISPR-associated protein 9; COX-2, cyclooxygenase 2; CRISPR, clustered regularly interspaced short palindromic repeat; HBSS, Hanks' balanced salt solution;ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; IL-1β, interleukin-1β; KO, knockout; MSC, mesenchymal stem cell; NK, natural killer; NKT, natural killer T; PE, phycoerythrin; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.The activation of natural killer (NK) cells in the liver inhibits engraftment of intraportally transplanted islets. We attempted to modulate the activity of NK cells by cotransplanting mesenchymal stem cells (MSCs) with islets in mice. We first investigated the ability of MSCs to secrete prostaglandin E2 , a predominant inhibitor of NK cell function, in various combinations of inflammatory cytokines. Notably, we found that prostaglandin E2 production was partially delayed in MSCs activated by inflammatory cytokines in vitro, whereas liver NK cells were activated early after islet transplant in vivo. Accordingly, preactivated MSCs, but not naive MSCs, substantially suppressed the expression of activation markers in liver NK cells after cotransplant with islets. Similarly, cotransplant with preactivated MSCs, but not naive MSCs, markedly improved the survival of islet grafts. These results highlight MSC cotransplant as an effective and clinically feasible method for enhancing engraftment efficiency.

Protecting islet functional viability using mesenchymal stromal cells

“…MSCs protect islets from an inflammatory, immunogenic host environment by two distinct mechanisms: suppression of host immune responses through regulation of immune cells, and direct protection of islet cells from inflammatory insults. In mouse models of diabetes, cotransplantation with MSCs is associated with inhibition of natural killer cell activation, inhibition of effector T‐cell proliferation and Th1 pro‐inflammatory cytokine production, and enhanced regulatory T‐cell activity 36‐38 . The immunosuppressive proteins matrix metalloproteinases 2 and 9 (MMP‐2 and ‐9) are commonly implicated in the cytoprotective effects of MSCs, and inhibition of MMP‐2 and MMP‐9 activity with SB3CT prevented cotransplanted MSCs from suppressing effector T‐cell proliferation and thus increased rejection of the allogenic islet graft 39 .…”

Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease

“…NK cells and MSCs also have a bi-directional role in regulating and in uencing NK cell activity. Pre-activated MSCs were found to signi cantly inhibit the expression of activation markers in hepatic NK cells after cotransplantation with pancreatic islets to regulate NK cell activity (83). Meanwhile, NK cells can also promote the homing effect of MSCs.…”

<p>Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets</p>

“…Mesenchymal stem cells (MSCs) are widely used to be co-transplanted with islets. [35][36][37][38][39] When co-transplanted with islets in recipients, MSCs can promote angiogenesis in situ to prevent hypoxia and to attenuate immune rejection. MSCs can suppress various immune cells such as NK cells, macrophages, neutrophils, and T cells.…”

“…MSCs can suppress various immune cells such as NK cells, macrophages, neutrophils, and T cells. 35,[40][41][42][43] Moreover, it was identified that MSCs could accelerate the maturation of neonatal porcine islets, which benefits the development of islets xenograft. 39 The establishment of immune tolerance to islet grafts, is a significant strategy for inducing acceptance of histocompatibility complex (MHC)mismatched allografts without compromising the host's immune system.…”